National Advisory Council Meeting - September 11-13, 2011

Monday, September 12, 2011

NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM

Summary of the 128th Meeting

The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 128th meeting at 3:00 p.m. on September 12, 2011, at Building 1, National Institutes of Health, Bethesda, Maryland, in closed session for a review of grant applications. The meeting recessed at 4:00 p.m. The Council reconvened on September 13, 2011, at 9:00 a.m. Dr. Abraham Bautista, Director, Office of Extramural Activities, presided over the closed session. In accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C. and 10(d) of Public Law 92-463, the closed session on September 12, 2011, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. Dr. Kenneth Warren, Acting Director, NIAAA, presided over the Council’s open session on September 13, 2011.

More than 40 observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.

Call to Order

Dr. Kenneth Warren called the open session of the 128th meeting of the Council to order at 9:00 a.m. on Tuesday, September 13, 2011, and welcomed participants. Dr. Warren acknowledged the contributions of Council members whose terms of service were coming to an end: Drs. Lynnell Klassen, David Crabb, and Deborah Hasin. Council members, NIAAA senior staff, and guests introduced themselves.

Legislation, budget, and policy. NIAAA’s FY 2011 budget of $458.3 million reflects a $4.1 million decrease (0.8%) from FY 2010. In FY 2011 NIAAA supported 683 research project grants, including 147 new and competing awards, for a total of $263.6 million. In FY 2010 NIAAA had supported 706 research project grants, of which 189 were new and competing—a group of awards typically sensitive to budget reductions. Support for FY 2011 noncompeting research project grants declined by 1%. Congressional action on the FY 2012 budget was anticipated to begin after the start of the fiscal year.

NIAAA staff honors and personnel. Dr. Peter Silverman received NIAAA’s Martin K. Trusty Award for Excellence in Management. The American College of Cardiology has elected Dr. Pal Palcher as a Fellow. Dr. Markus Heilig has been selected to give the 2010 Archibald Lecture at the Centre for Addiction and Mental Health in Toronto. Dr. Joseph Hibbeln received the 2011 Albert Cogan Lectureship Award at the University of Missouri at Columbia.

Two employees have joined NIAAA on detail. Dr. Lynn Morin works in the Health Disparities Program, and Ms. Jenny Czajkowski serves as NIAAA’s Acting Deputy Executive Officer.

Mechanisms of Ethanol-Induced Fatty Liver Disease

Dr. David Crabb, Director, Indiana Alcohol Research Center, Department of Medicine, Indiana University, reviewed the past decade’s findings on the effects of alcohol in the liver. Dr. Crabb explained that any human or animal that drinks heavily can develop a fatty liver, generally a reversible condition but on the pathway to either alcoholic hepatitis or cirrhosis, which likely facilitates the transition to inflammation and cirrhosis.

Dr. Crabb stated that studies in 1970s showed that ethanol itself can cause fatty liver by inhibition of fatty acid oxidation, and that stimulation of fatty acid synthesis induces lipogenic enzymes. A side experiment showed that in fatty HeLa cells that expressed alcohol dehydrogenase, there was more triglyceride even in the absence of added alcohol, and if alcohol were present in the medium, the fat accumulated. The finding confirmed the need for alcohol metabolism in the effects he described through the balance of the presentation. In examining metabolism and collection of lipid, researchers found that adding alcohol to cells that can metabolize alcohol raised the lactate/pyruvate ratio; linoleic acid oxidation was reduced; and triglyceride synthesis was increased—findings consistent with then-current knowledge about the liver.

Dr. Crabb’s experiments on the effect of alcohol on the reporter constructs that respond to the alpha form of peroxisome proliferator activated receptors (PPARα) and on the ability of nuclear receptors to bind DNA revealed that alcohol inhibited the PPARα system. In vivo work with mice showed that a PPARα agonist reverses fatty liver despite continued alcohol use, leading the researchers to consider the plausibility of treating for fatty liver individuals who do not abstain from drinking.

This work led to the question of whether alcohol alters the function of other transcription factors involved in lipid metabolism. One form of the sterol response element binding protein (SREBP-1c) plays a role in the synthesis of fatty acids and triglycerides. When this is over-expressed in the liver of a mouse, the animal develops a massive fatty liver. The researchers used a number of enzymes produced by this transcription factor as a marker of this activity. Dr. Crabb also found that certain concentrations of alcohol generated substantial activation of a reporter responsive to SREBP in two liver-derived cell lines that have at least modest ability to metabolize alcohol, in contrast to a control cell line insensitive to alcohol’s effects. In vivo experiments confirmed alcohol’s effect on the SREBP pathway. The battery of enzymes involved in fatty liver synthesis was induced in the range of twofold in mice fed alcohol. Dr. Crabb stated that this explains an earlier observation that the enzymes were induced by chronic alcohol feeding.

Dr. Crabb took an interest in AMP-dependent protein kinase (AMPK), which increases fatty liver oxidation and decreases lipogenesis and cholesterol synthesis. He found that alcohol feeding inhibits AMPK activity in hepatic fat metabolism, but the mechanism that connects ethanol to the many pathways to fatty liver, including PPARα, is not fully understood. Dr. Crabb noted the need for care in determining how alcohol inhibits AMPK because of AMPK’s sensitivity to levels of AMP.

Recent work revealed that by inhibiting protein phospatase 2A (PPA2) with okadaic acid or siRNAs, the inhibition of AMPK by alcohol can be blocked to some extent. A collaborator who performed mass spectrometric analysis of lipids found that alcohol increased ceramide; Dr. Crabb demonstrated that by adding ceramide to cultured cells, PP2A can be turned on and AMPK inhibited. He hypothesizes that the sphingomyelinase enzyme plays a role in alcohol’s effect on ceramide—feeding alcohol activates acidic sphingomyelinase (ASMase), which can be inhibited with imipramine, which in turn blocks the activation of both PP2A and AMPK. The research group is working backwards to learn whether this pathway has an effect on PPARα.

Dr. Crabb explained that carbohydrate response element binding protein (ChREBP), another protein important for lipogenesis, also works synergistically with SREBP. Knocking out ChREBP results in much less stimulation of lipogenesis from other stimuli. ChREBP is subject to phosphorylation, including by AMPK, and when AMPK phosphorylates ChREBP, it is less active—consistent with findings that this enzyme helps burn fat and not make lipids, and that PP2A is involved in the activation of ChREBP. If this factor is dephosphorylated, it can move into the nucleus and carry out its stimulatory activity. Researchers found that alcohol feeding in animals caused a shift of ChREBP into the nucleus and out of the cytosol; the liver pyruvate kinase message is increased more than fourfold in mouse livers. Another lipogenetic factor appears to increase the rate of fat synthesis in the liver.

Explaining his yet unpublished work, Dr. Crabb stated that at least in cultured cells, imipramine inhibits ASMase and reduces ceramide. Ethanol increased ASMase activity in liver extracts, and a modest reduction occurred upon adding imipramine. The alcohol-fed animals had a higher level of PP2A activity, which was reduced modestly by feeding imipramine with the liquid diet. Ceramide levels rose with alcohol and fell with imipramine, and the alcohol-plus-imipramine diet reduced triglycerides.

In summarizing his studies, Dr. Crabb explained that alcohol inhibits PPARα activity, generates ceramide, activates PP2A, leads to inhibition of AMPK, and may play a role in activating SREBP/ChREBP. Future directions should involve less exploration for additional pathways, but rather should determine why fatty liver transitions to alcoholic hepatitis or cirrhosis to learn which aspects of the signaling pathways might be responsible for the sensitization of liver cells to subsequent stresses, such as oxidative stress or exposure to TNFα after endotoxin levels rise in the portal brain. With such knowledge, researchers could try to interrupt the pathways to alcohol hepatitis and cirrhosis, and to make the liver more robust.

Discussion. Dr. Scott Friedman inquired about genetic variability in the propensity to develop fat, given similar ethanol ingestion. Dr. Crabb responded that no identified candidate gene is particularly strong. A difficult GWAS study soon will try to identify additional genes for cirrhosis in a systematic, nonbiased approach. In response to a question from Dr. Gyongi Szabo, Dr. Crabb stated that a number of lines of evidence show that activation of PPARα is anti-inflammatory in the vascular system. He plans to follow up with ceramide, which can turn on other stress kinases that play roles in inflammatory pathways. Several kinases are turned on in alcohol feeding and reduced by imipramine treatment. Dr. Crabb explained to Dr. John Krystal that he has not looked at the range of possible cellular targets for imipramine. Asked by Dr. Samir Zakhari to speculate on the relative contribution of PPARα and PPARγ (gamma), Dr. Crabb stated that he found a small but statistically significant inhibition by alcohol of PPARγ in transfected cells. He stated that Galli has found effects of acetaldehyde exposure to stellate cells on their PPARγ that he proposed were involved in their going from a fat-storing to non-fat-storing fibrogenic cell. In the liver the amount of PPARγ is lower and its roles are fewer, but not minor.

Consideration of the Minutes of the Meeting of June 8–9, 2011, and Future Meeting Dates

Council members unanimously approved the minutes of the Council meeting of June 8–9, 2011. Future Council meetings are planned for February 8–9, 2012; June 6–7, 2012; September 19–20, 2012; February 6–7, 2013; June 12–13, 2013; September 18–19, 2013; February 5–6, 2014; June 4–5, 2014; and September 10–11, 2014.

Alcohol: Psychiatric Epidemiologic Perspective

Dr. Deborah Hasin, Professor of Clinical Epidemiology, College of Physicians and Surgeons, Columbia University, discussed alcohol from a psychiatric epidemiology perspective, which considers distribution, determinants, and course of psychiatric conditions in different populations. She focused on alcohol use disorders, for which drinking is one of a number of risk factors. Overlapping areas of study include nosology (concept and ‌measurement), etiology (risk factors), natural history, and service delivery.

Dr. Hasin explained that Edwards described Alcohol Dependence Syndrome (ADS) based on close observation of patients. Dependence was considered one axis of a bi-axial concept, with consequences of drinking a separate axis. ADS was highly influential in defining alcohol use disorders in the DSM-II-R and the DSM-IV, which considers alcohol dependence and abuse to be different disorders. The DSM-5 workgroup will decide whether abuse and dependence should remain as distinct disorders or combined. The current diagnostic system has bred confusion about severity, an assumption that abuse is prodromal to dependence, and an assumption that all cases of dependence meet the criteria for abuse among, other definitional problems. Consistent findings show that alcohol abuse is a risk factor for depression and that alcohol abuse either remains as abuse or ends. Using NESARC data, Saha, Grant, and colleagues (2007) show that severity of abuse and dependence do not align separately, and Dr. Hasin’s (2010) work in Israel reveals similar results. Consequently, the DSM-5 workgroup has decided (to date) to combine abuse and dependence to create a single disorder. Although the prevailing public view is that males are more at risk for alcohol disorders than females, NESARC data show that the gender gap has narrowed for both dependence and abuse with each succeeding age cohort. Data show also that alcohol dependence, but not alcohol abuse, has a strong relationship with psychiatric comorbidity.

Dr. Hasin discussed findings from a study of micro-level risk factors and gene/environment interaction in Israel, undertaken there because of the high prevalence of ADH1B, a gene with the strongest demonstrated relationship to alcohol phenotypes. The protective allele is rare in European samples, but Jewish samples have better distribution. The study examined the drinking patterns of immigrants from the former Soviet Union in the 1990s, a group that drank much more than other Israelis. Dr. Hasin and colleagues collected data on other stressors, including early child maltreatment and such adult exposures as the 2006 war with Lebanon, to determine whether gene phenotype relationships differed with different environmental exposures. Major findings to date include a significant difference in weekly binge drinking between Russians and other groups, with a stronger (but not significant) gene phenotype relationship among Russian immigrants than in other groups. In people not exposed to childhood stressors, ADH1B genetic effects were weak, but exposure had a strong significant relationship to the alcohol phenotype.

Dr. Hasin’s work on state-level and birth cohort–level effects on risks for drinking behavior revealed that a state beer tax is inversely related to risk for alcohol dependence and for marijuana use, and birth cohort drinking norms are inversely related to various drinking and marijuana use patterns.

Turning to a discussion of natural history, Dr. Hasin noted that many studies look at the risk that psychiatric disorders pose for chronic alcohol dependence, mainly major depression and anxiety disorders. NESARC data show that about 30% of cases remained fully symptomatic for alcohol dependence during 3 years of follow-up. When controlled solely for demographics, some disorders were predicted, but in controlling for comorbidity, all relationships disappeared. Antisocial disorder, borderline personality disorder, and schizotypal disorder predicted persistent, chronic alcohol disorders regardless of controls. Dr. Hasin suggested the utility of considering other domains of personality dysfunction whose risk factors and persistence differ over time.

NESARC data revealed no progress from the early 1990s through 2002 in improving treatment rates of individuals with alcohol disorders, in contrast with improved rates of treatment for drug use disorders. Dr. Hasin stated that getting treatment is less likely among people with stigmatizing attitudes towards alcohol disorders, and financial considerations were not cited as a reason not to get treatment. Attitudinal factors might have greater impact.

Dr. Hasin’s research on securing treatment in primary care settings for people with drinking problems and HIV involves automated telephone interactive voice responses (IVR) to enhance the effects of a brief motivational interview. Following the intervention in this randomized controlled trial, participants placed an IVR call daily and reported on their drinking behavior and several other factors. The study found that drinking declined over all conditions, regardless of the intervention. Among participants who met criteria for dependence at baseline, the experimental group improved significantly more than the other groups. Next steps include developing smart phone applications able to provide moving visual images and an opportunity to enter responses to questions.

Discussion. To a question from Dr. Andrew Heath, Dr. Hasin responded that parental alcoholism is the proxy in the Israeli study for genetic exposure. Dr. Krystal inquired whether the studies of psychiatric disorders looked at clusters of schizotypal symptoms or at family history. Dr. Hasin responded that while her study did not include family history of psychotic disorders, an exploratory focus on symptoms might identify treatment hooks. Dr. Krystal’s suggested that there should be a study that excludes people with schizotypal personality disorders with a family history of substance abuse to learn the relevance of that history to risk for alcohol and substance use disorders. She agreed and stated that NESARC data show an association of schizotypal personality disorder with alcohol and drug disorders.

Responding to Dr. Spear’s questions, Dr. Hasin described details of the DSM-5 workgroup’s provisional decision to combine alcohol and abuse into a single diagnostic category. Empirical evidence from population studies, but few clinical samples to date, strongly supports their combination. The new criteria would delete substance-related legal problems and add craving to the 11 other criteria; the greater the number of criteria, the more severe the condition, with a threshold of two or more criteria for a diagnosis—although no empirical evidence exists for that cut point. Dr. Hasin’s samples were similar for adolescents and adults. Dr. Vivian Faden questioned the reason for the change from the DSM-IV definition, to which Dr. Hasin responded that the threshold accommodates treatment decisions and funding decisions based on the prevalence rate. To Dr. Warren’s question about craving, Dr. Hasin stated that craving is among the criteria in ICD-10; clinicians support adding craving to the DSM-5; and adding the criteria perturbs nothing. Nevertheless, measurement of craving is affected by the questions asked, and measures of craving do not appear in large datasets.

To Dr. Kathleen Grant’s observation that legal consequences may be valuable as a deterrent early in the course of drinking and not appropriate as a criterion on the abuse spectrum, Dr. Hasin explained that legal consequences are rarely reported, that this criterion does not contribute useful information, and that failing to fulfill major role functions is associated with chronic alcoholics in treatment. She acknowledged the need for different questions to elicit information on deterrence.

Public Comment

Ms. Adrienne Brown, Alcoholics Anonymous (AA) World Services, announced recent publication of the pamphlet “Alcoholics Anonymous for the Alcoholic with Special Needs,” the revised “AA Member Medications and Other Drugs,” and a new literature catalog. The “Big Book” and “12 Steps, 12 Traditions” will be available as e-books at www.aa.org. The free materials are available in English, French, and Spanish, and online availability of publications is increasing. Dr. Andrea Barthwell stated that she uses AA pamphlets in her practice.

Council Member Round Table

In response to Dr. Hasin’s question about developing an action plan for the NIAAA/National Institute on Drug Abuse (NIDA) reorganization, Dr. Warren stated that a group of NIAAA Council members will be convened to develop recommendations and to participate in other advisory activities. While organizational structure remains the purview of the National Institutes of Health (NIH), Councils provide advice on the science. In doing so, he observed that it is reasonable for the Council to request certain types of information to facilitate formulating their advice. Dr. Warren stated that NIDA likely will form a counterpart group and the two groups will interact. Dr. Barthwell asserted that it is essential for the Council to discuss how NIAAA’s portfolio is addressed and the scientific matters that might arise. Noting that that is the goal of the group to be formulated, Dr. Warren stated that to date NIH had released no information to which the Council could react, but that opportunities will open for expert input. To a question from Dr. Suzanne de la Monte, Dr. Warren explained that key people from NIAAA, NIDA, the National Cancer Institute, and other relevant Institutes had opportunities to offer initial input, and that he had had an opportunity to advocate for the inclusion of certain areas of science. Dr. Barthwell emphasized that the specific request from the NIAAA Council is to meet and comment.

Adjournment

Dr. Warren adjourned the meeting at 11:45 p.m.

CERTIFICATION

I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.

/s/

Kenneth R. Warren, Ph.D.
Acting Director
National Institute on Alcohol Abuse and Alcoholism
and
Chairperson
National Advisory Council on Alcohol Abuse and Alcoholism

/s/

Abraham P. Bautista, Ph.D.
Director
Office of Extramural Activities
and
Executive Secretary
National Advisory Council on Alcohol Abuse and Alcoholism